Severe injury and infection are leading causes of morbidity and mortality among adults. Such severe conditions evoke both pro-inflammatory and anti-inflammatory responses at the systemic and tissue levels. While systemic anti-inflammation is directed initially by hormonal and autonomic influences, the effectiveness of these systemic anti-inflammatory mechanisms dissipates during prolonged stressful conditions. In the context of a subsequent (e.g. infectious) challenge, alternative anti-inflammatory pathway(s) must compensate for the diminished regulatory influences exerted by endocrine hormones, such as cortisol and catecholamines. In the current proposal, we hypothesize that competent vagal autonomic pathways assume greater significance for dampening inflammatory stress during prolonged recovery. In modeling the human reponse to initially sterile (hormone infusion) and subsequent inflammatory (endotoxinemia) stressors, we have noted a diminution of endocrine mediated anti-inflammatory responsiveness. Hence, we propose that any acquired vagal autonomic dysfunction (VAD) becomes a limiting factor for dampening pro-inflammatory responses to secondary stressful stimulus, such as endotoxin. In Specifc Aim #1, we will A) model a period of sterile stress (via stress hormone infusion) to ascertain the role of vagal autonomic function (by heart rate variability determinations) upon endotoxin-induced systemic pro- and anti-inflammatory responses in humans. We also will, B) utilize an agonist of the vagal cholinergic anti-inflammatory pathway to ascertain the influence of this agent upon inflammatory responses to endotoxin following a period of hormone stress. We have recently documented acquired VAD during intestinal nutrient deprivation. In Specifc Aim #2, we will utilize this human model to ascertain acute intestinal nutrient (high-fat) stimulation on vagal tone and the response to endotoxin. In Specific Aim #3, we will determine the incidence and consequences of sterile stress (trauma and surgery) induced alterations of inflammatory balance and VAD in critically-ill patients at risk for a secondary stimulus, such as infection and/or organ failure. Relevance to Public Health: The proposed studies will clarify the clinical contexts in which vagal autonomic dysfunction contributes to morbidity and mortality in severely stressed patients. The proposed low-risk interventions will also define opportunities to enhance vagally regulated anti-inflammatory responses.